Combination of bcma-directed t cell therapy and an immunomodulatory compound

Abstract

Provided herein are methods, compositions and uses for treating subjects with diseases and conditions, such as those involving or associated with B cell maturation antigen (BCMA), involving administration of a T cell therapy, such as a BCMA-targeted T cell therapy, e.g. anti-BCMA CART cells, in combination with (S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2, 6-dione, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer or racemic mixtures thereof, and compositions thereof, or in combination with (S)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer or racemic mixtures thereof, and compositions thereof. The T cell therapy includes cells that express recombinant receptors such as chimeric antigen receptors (CARs) directed against BCMA. In some embodiments, the disease or condition is a multiple myeloma, such as relapsed or refractory multiple myeloma.

What is claimed: 
     
         1 . A method of treating multiple myeloma, the method comprising:
 (a) administering a T cell therapy to a subject having a relapsed or refractory multiple myeloma (R/R MM), said T cell therapy comprising a dose of genetically engineered T cells expressing a chimeric antigen receptor (CAR) that specifically binds to BCMA; and   (b) administering to the subject an immunomodulatory compound that is (S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione having the following structure:   
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof,
 wherein administration of the immunomodulatory compound is initiated after administration of the T cell therapy. 
 
     
     
         2 . The method of  claim 1 , wherein prior to initiation of the administration of the T cell therapy and the immunomodulatory compound, the subject has received one or more prior therapies for treating the R/R MM, said one or more prior therapies comprising an immunomodulatory agent. 
     
     
         3 . A method of treating multiple myeloma, the method comprising:
 (a) administering a T cell therapy to a subject having a relapsed or refractory multiple myeloma (R/R MM), said T cell therapy comprising a dose of genetically engineered T cells expressing a chimeric antigen receptor (CAR) that specifically binds to BCMA; and   (b) administering to the subject an immunomodulatory compound that is (S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione having the following structure:   
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof;
 wherein prior to initiation of the administration of the T cell therapy and the immunomodulatory compound, the subject has received one or more prior therapies for treating the R/R MM, said one or more prior therapies comprising an immunomodulatory agent. 
 
     
     
         4 . The method of any of  claims 1 - 3 , wherein the immunomodulatory compound is or comprises a pharmaceutically acceptable salt of (S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione. 
     
     
         5 . The method of any of  claims 1 - 3 , wherein the immunomodulatory compound is or comprises a hydrate of (S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione. 
     
     
         6 . The method of any of  claims 1 - 3 , wherein the immunomodulatory compound is or comprises a solvate of (S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione. 
     
     
         7 . The method of any of  claims 1 - 3 , wherein the immunomodulatory compound is or comprises (S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione. 
     
     
         8 . A method of treating multiple myeloma, the method comprising:
 (a) administering a T cell therapy to a subject having a relapsed or refractory multiple myeloma (R/R MM), said T cell therapy comprising a dose of genetically engineered T cells expressing a chimeric antigen receptor (CAR) that specifically binds to BCMA; and   (b) administering to the subject an immunomodulatory compound that is (S)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile having the following structure:   
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof,
 wherein administration of the immunomodulatory compound is initiated after administration of the T cell therapy. 
 
     
     
         9 . The method of  claim 8 , wherein prior to initiation of the administration of the T cell therapy and the immunomodulatory compound, the subject has received one or more prior therapies for treating the R/R MM, said one or more prior therapies comprising an immunomodulatory agent. 
     
     
         10 . A method of treating multiple myeloma, the method comprising:
 (a) administering a T cell therapy to a subject having a relapsed or refractory multiple myeloma (R/R MM), said T cell therapy comprising a dose of genetically engineered T cells expressing a chimeric antigen receptor (CAR) that specifically binds to BCMA; and   (b) a administering to the subject an immunomodulatory compound that is (S)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile having the following structure:   
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, wherein prior to initiation of the administration of the T cell therapy and the immunomodulatory compound, the subject has received one or more prior therapies for treating the R/R MM, said one or more prior therapies comprising an immunomodulatory agent. 
       
     
     
         11 . The method of any of  claims 8 - 10 , wherein the immunomodulatory compound is or comprises a pharmaceutically acceptable salt of (S)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile. 
     
     
         12 . The method of any of  claims 8 - 10 , wherein the immunomodulatory compound is or comprises a hydrate of (S)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile. 
     
     
         13 . The method of any of  claims 8 - 10 , wherein the immunomodulatory compound is or comprises a solvate of (S)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile. 
     
     
         14 . The method of any of  claims 8 - 10 , wherein the immunomodulatory compound is or comprises (S)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile. 
     
     
         15 . The method of any of  claims 1 - 14 , wherein the subject has relapsed or been refractory following at least 3 or at least 4 prior therapies for multiple myeloma. 
     
     
         16 . The method of any of  claims 1 - 15 , wherein the subject has received, and has relapsed or been refractory to, three or more therapies selected from among:
 autologous stem cell transplant (ASCT);   an immunomodulatory agent;   a proteasome inhibitor; and   an anti-CD38 antibody; unless the subject was not a candidate for or was contraindicated for one or more of the therapies.   
     
     
         17 . The method of any of  claims 2 - 7  and  9 - 16 , wherein the immunomodulatory agent is selected from among thalidomide, lenalidomide and pomalidomide. 
     
     
         18 . The method of  claim 16 , wherein the proteasome inhibitor is selected from among bortezomib, carfilzomib and ixazomib. 
     
     
         19 . The method of  claim 16 , wherein the anti-CD38 antibody is or comprises daratumumab. 
     
     
         20 . The method of any of  claims 1 - 19 , wherein, at the time of administration, the subject has been refractory to or not responded to bortezomib, carfilzomib, lenalidomide, pomalidomide and/or an anti-CD38 monoclonal antibody. 
     
     
         21 . The method of any of  claims 1 - 20 , wherein, at the time of administration, the subject has IMWG high risk cytogenetics. 
     
     
         22 . The method of any of  claims 1 - 2 ,  4 - 9 , and  11 - 21 , wherein administration of the immunomodulatory compound is initiated at or prior to peak expansion of the T cell therapy in the subject. 
     
     
         23 . The method of  claim 22 , wherein peak expansion of the T cell therapy is between at or about 11 days and at or about 15 days after administering the T cell therapy. 
     
     
         24 . The method of any of  claims 1 - 2 ,  4 - 9 , and  11 - 23 , wherein administration of the immunomodulatory compound is initiated between at or about 1 day and at or about 15 days, inclusive, after administering the T cell therapy. 
     
     
         25 . The method of any of  claims 1 - 2 ,  4 - 9 , and  11 - 24 , wherein administration of the immunomodulatory compound is initiated between at or about 1 day and at or about 11 days, inclusive, after administering the T cell therapy. 
     
     
         26 . The method of any of  claims 1 - 2 ,  4 - 9 , and  11 - 25 , wherein the administration of the immunomodulatory compound is initiated between at or about 8 days and at or about 15 days, inclusive, after administering the T cell therapy. 
     
     
         27 . The method of any of  claims 1 - 2 ,  4 - 9 , and  11 - 26 , wherein administration of the immunomodulatory compound is initiated at or about 1 day after administering the T cell therapy. 
     
     
         28 . The method of any of  claims 1 - 2 ,  4 - 9 , and  11 - 26 , wherein administration of the immunomodulatory compound is initiated at or about 8 days after administering the T cell therapy. 
     
     
         29 . The method of any of  claims 1 - 2 ,  4 - 9 , and  11 - 26 , wherein the administration of the immunomodulatory compound is initiated at or about 15 days after administering the T cell therapy. 
     
     
         30 . The method of any of  claims 1 - 2 ,  4 - 9 , and  11 - 21 , wherein the administration of the immunomodulatory compound is initiated about 14 to about 35 days after initiation of administration of the T cell therapy. 
     
     
         31 . The method of any of  claims 1 - 2 ,  4 - 9 ,  11 - 21 , and  30 , wherein the administration of the immunomodulatory compound is initiated about 21 to about 35 days after initiation of administration of the T cell therapy. 
     
     
         32 . The method of any of  claims 1 - 2 ,  4 - 9 ,  11 - 21 ,  30 , and  31 , wherein the administration of the immunomodulatory compound is initiated about 21 to about 28 days after initiation of administration of the T cell therapy. 
     
     
         33 . The method of any of  claims 1 - 2 ,  4 - 9 ,  11 - 21 , and  30 - 32 , wherein the administration of the immunomodulatory compound is initiated at or about 21 days, at or about 22 days, at or about 23 days, at or about 24 days, at or about 25 days, at or about 26 days, at or about 27 days, or at or about 28 days after initiation of administration of the T cell therapy. 
     
     
         34 . The method of any of  claims 1 - 2 ,  4 - 9 ,  11 - 21 , and  30 - 33 , wherein the administration of the immunomodulatory compound is initiated at or about 28 days after the initiation of the administration of the T cell therapy. 
     
     
         35 . The method of any of  claims 3 - 7  and  10 - 21 , wherein the immunomodulatory compound is administered from or from about 0 to 30 days, 0 to 15 days, 0 to 6 days, 0 to 96 hours, 2 hours to 15 days, 2 hours to 6 days, 2 hours to 96 hours, 6 hours to 30 days, 6 hours to 15 days, 6 hours to 6 days, 6 hours to 96 hours, 12 hours to 30 days, 12 hours to 15 days, 12 hours to 6 days, or 12 hours to 96 hours prior to initiation of the T cell therapy. 
     
     
         36 . The method of any of  claims 3 - 7 ,  10 - 21 , and  35 , wherein the immunomodulatory compound is administered no more than about 96 hours, 72 hours, 48 hours, or 24 hours prior to initiation of the T cell therapy. 
     
     
         37 . The method of any of  claims 1 - 36 , wherein the immunomodulatory compound is administered at least once daily in a cycle regimen. 
     
     
         38 . The method of  claim 37 , wherein the immunomodulatory compound is administered in a cycle regimen comprising the administration of the immunomodulatory compound for a plurality of consecutive days followed by a rest period during which the immunomodulatory compound is not administered. 
     
     
         39 . The method of  claim 38 , wherein the plurality of consecutive days is up to 21 days. 
     
     
         40 . The method of any of  claims 37 - 39 , wherein the cycle regimen is a four-week (28-day) cycle wherein the immunomodulatory compound is administered daily for three consecutive weeks in the four-week cycle and is not administered for the last week. 
     
     
         41 . The method of any of  claims 37 - 40 , wherein the cycle regimen is a four-week (28-day) cycle wherein the immunomodulatory compound is administered daily for days 1 through 21 of each four-week cycle. 
     
     
         42 . The method of any of  claims 37 - 41 , wherein the cycle regimen is repeated a plurality of times. 
     
     
         43 . The method of any of  claims 1 - 42 , wherein the immunomodulatory compound is administered up to at or about six months after initiation of administration of the T cell therapy. 
     
     
         44 . The method of any of  claims 1 - 43 , wherein the immunomodulatory compound is administered in an amount that is at or about 0.1 mg to about 1.0 mg per day. 
     
     
         45 . The method of any of  claims 1 - 44 , wherein the immunomodulatory compound is administered in an amount that is at or about 0.3 mg to about 0.6 mg. 
     
     
         46 . The method of any of  claims 1 - 45 , wherein the immunomodulatory compound is administered in an amount that is at or about 0.3 mg. 
     
     
         47 . The method of any of  claims 1 - 45 , wherein the immunomodulatory compound is administered in an amount that is at or about 0.45 mg. 
     
     
         48 . The method of any of  claims 1 - 45 , wherein the immunomodulatory compound is administered in an amount that is at or about 0.6 mg. 
     
     
         49 . The method of any of  claims 1 - 48 , wherein the immunomodulatory compound is administered orally. 
     
     
         50 . The method of any of  claims 1 - 49 , wherein at the time of the initiation of the administration of the immunomodulatory compound, the subject does not exhibit a severe toxicity following the administration of the T cell therapy. 
     
     
         51 . The method of  claim 50 , wherein:
 the severe toxicity is severe cytokine release syndrome (CRS), optionally grade 3 or higher, prolonged grade 3 or higher or grade 4 or 5 CRS; and/or   the severe toxicity is severe neurotoxicity, optionally grade 3 or higher, prolonged grade 3 or higher or grade 4 or 5 neurotoxicity.   
     
     
         52 . The method of any one of  claims 1 - 51 , wherein the administration of the immunomodulatory compound is suspended and/or the cycling regimen is modified if the subject exhibits a toxicity following the administration of the immunomodulatory compound, optionally a hematologic toxicity. 
     
     
         53 . The method of  claim 52 , wherein the toxicity is selected from severe neutropenia, optionally febrile neutropenia, prolonged grade 3 or higher neutropenia. 
     
     
         54 . The method of any of  claims 1 - 53 , wherein the administration of the immunomodulatory compound:
 reverses an exhaustion phenotype in CAR-expressing T cells in the subject;   prevents, inhibits or delays the onset of an exhaustion phenotype in CAR-expressing T cells in the subject;   or reduces the level or degree of an exhaustion phenotype in CAR-expressing T cells in the subject; or   reduces the percentage, of the total number of CAR-expressing T cells in the subject, that have an exhaustion phenotype.   
     
     
         55 . The method of any of  claims 1 - 54 , wherein following administration of the immunomodulatory compound or initiation thereof, the subject exhibits a restoration or rescue of an antigen- or tumor-specific activity or function of CAR-expressing T cells in said subject, optionally wherein said restoration, rescue, and/or initiation of administration of said compound, is at a point in time after CAR-expressing T cells in the subject or the in the blood of the subject have exhibited an exhausted phenotype. 
     
     
         56 . The method of any of  claims 1 - 55 , wherein the administration of the immunomodulatory compound comprises administration at an amount, frequency and/or duration effective to:
 (a) effect an increase in antigen-specific or antigen receptor-driven activity of naïve or non-exhausted T cells in the subject, which optionally comprise T cells expressing said CAR, following exposure of the T cells to BCMA or to an agonist of the CAR, optionally wherein the agonist is an anti-idiotypic antibody, as compared to the absence of said administration of said compound; or   (b) prevent, inhibit or delay the onset of an exhaustion phenotype, in naïve or non-exhausted T cells T cells in the subject, which optionally comprise T cells expressing said CAR, following exposure of the T cells to BCMA or to an agonist of the CAR, optionally wherein the agonist is an anti-idiotypic antibody, as compared to the absence of said administration of said compound; or   (c) reverse an exhaustion phenotype in exhausted T cells, optionally comprising T cells expressing said CAR, in the subject, as compared to the absence of said administration of said subject.   
     
     
         57 . The method of any of  claims 1 - 56 , wherein at the time of the administration of the immunomodulatory compound an exhausted phenotype of one or more of the CAR-expressing T cells, or a marker or parameter indicative thereof, has been detected or measured in the subject or in a biological sample from the subject. 
     
     
         58 . The method of  claim 57 , wherein at least at or about 10%, at least at or about 20%, at least at or about 30%, at least at or about 40%, or at least at or about 50% of the total CAR-expressing T cells in a biological sample from the subject has an exhausted phenotype. 
     
     
         59 . The method of  claim 57  or  claim 58 , wherein greater than at or about 10%, greater than at or about 20%, greater than at or about 30%, greater than at or about 40%, or greater than at or about 50% of the CAR-expressing T cells in a biological sample from the subject has an exhausted phenotype compared to the percentage of the CAR-expressing T cells having the exhausted phenotype in a comparable biological sample at a prior time point. 
     
     
         60 . The method of any of  claims 57 - 59 , wherein the exhaustion phenotype, with reference to a T cell or population of T cells, comprises:
 an increase in the level or degree of surface expression on the T cell or T cells, or in the percentage of T said population of T cells exhibiting surface expression, of one or more exhaustion marker, optionally 2, 3, 4, 5 or 6 exhaustion markers, compared to a reference T cell population under the same conditions; or   a decrease in the level or degree of an activity exhibited by said T cells or population of T cells upon exposure to BCMA or an agonist of the CAR, optionally wherein the agonist is an anti-idiotypic antibody, compared to a reference T cell population, under the same conditions.   
     
     
         61 . The method of  claim 60 , wherein the increase in the level, degree or percentage is by greater than at or about 1.2-fold, at or about 1.5-fold, at or about 2.0-fold, at or about 3-fold, at or about 4-fold, at or about 5-fold, at or about 6-fold, at or about 7-fold, at or about 8-fold, at or about 9-fold, at or about 10-fold or more. 
     
     
         62 . The method of  claim 60 , wherein the decrease in the level, degree or percentage is by greater than at or about 1.2-fold, at or about 1.5-fold, at or about 2.0-fold, at or about 3-fold, at or about 4-fold, at or about 5-fold, at or about 6-fold, at or about 7-fold, at or about 8-fold, at or about 9-fold, at or about 10-fold or more. 
     
     
         63 . The method of any of  claims 60 - 62 , wherein the reference T cell population is a population of T cells known to have a non-exhausted phenotype, is a population of naïve T cells, is a population of central memory T cells, or is a population of stem central memory T cells, optionally from the same subject, or of the same species as the subject, from which the T cell or T cells having the exhausted phenotype are derived. 
     
     
         64 . The method of any of  claims 60 - 63 , wherein the reference T cell population (a) is a subject-matched population comprising bulk T cells isolated from the blood of the subject from which the T cell or T cells having the exhausted phenotype is derived, optionally wherein the bulk T cells do not express the CAR and/or (b) is obtained from the subject from which the T cell or T cells having the exhausted phenotype is derived, prior to receiving administration of a dose of T cells expressing the CAR. 
     
     
         65 . The method of any of  claims 60 - 64 , wherein the reference T cell population is a composition comprising a sample of the T cell therapy, or pharmaceutical composition comprising T cells expressing the CAR, prior to its administration to the subject, optionally wherein the composition is a cryopreserved sample. 
     
     
         66 . The method of any of  claims 60 - 65 , wherein one or more of the one or more exhaustion marker is an inhibitory receptor. 
     
     
         67 . The method of any of  claims 60 - 66 , wherein one or more of the one or more exhaustion marker is selected from among PD-1, CTLA-4, TIM-3, LAG-3, BTLA, 2B4, CD160, CD39, VISTA, and TIGIT. 
     
     
         68 . The method of any of  claims 60 - 67 , wherein the activity or is one or more of proliferation, cytotoxicity or production of one or a combination of inflammatory cytokines, optionally wherein the one or a combination of cytokines is selected from the group consisting of IL-2, IFN-gamma and TNF-alpha. 
     
     
         69 . The method of any of  claims 60 - 68 , wherein the exposure to BCMA or an agonist of the CAR, optionally wherein the agonist is an anti-idiotypic antibody, comprises incubation with BCMA or the agonist of the CAR. 
     
     
         70 . The method of  claim 69 , wherein the antigen is comprised on the surface of antigen-expressing target cells, optionally multiple myeloma cells or cell line. 
     
     
         71 . The method of any of  claims 1 - 70 , wherein the dose of T cells is between at or about 5×10 7  CAR+ T cells and at or about 1×10 9  CAR+ T cells. 
     
     
         72 . The method of any of  claims 1 - 70 , wherein the dose of T cells is between at or about 1×10 8  CAR+ T cells and at or about 1×10 9  CAR+ T cells. 
     
     
         73 . The method of any of  claims 1 - 70 , wherein the dose of T cells is at or about 1.5×10 8  cells or CAR+ T cells. 
     
     
         74 . The method of any of  claims 1 - 70 , wherein the dose of T cells is at or about 3×10 8  cells or CAR+ T cells. 
     
     
         75 . The method of any of  claims 1 - 70 , wherein the dose of T cells is at or about 4.5×10 8  cells or CAR+ T cells. 
     
     
         76 . The method of any of  claims 1 - 70 , wherein the dose of T cells is at or about 6×10 8  cells or CAR+ T cells. 
     
     
         77 . The method of any of  claims 1 - 76 , wherein the dose comprises CD3 +  CAR-expressing T cells. 
     
     
         78 . The method of any of  claims 1 - 77 , wherein the dose comprises a combination of CD4 +  T cells and CD8 +  T cells and/or a combination of CD4 +  CAR-expressing T cells and CD8 +  CAR-expressing T cells. 
     
     
         79 . The method of  claim 78 , wherein the ratio of CD4 +  CAR-expressing T cells to CD8 +  CAR-expressing T cells and/or of CD4 +  T cells to CD8 +  T cells, is or is approximately 1:1 or is between at or approximately 1:3 and at or approximately 3:1. 
     
     
         80 . The method of any of  claims 1 - 79 , wherein prior to the administration of the dose of T cells, the subject has received a lymphodepleting therapy comprising the administration of fludarabine at or about 20-40 mg/m 2  body surface area of the subject, optionally at or about 30 mg/m 2 , daily, for 2-4 days, and/or cyclophosphamide at or about 200-400 mg/m 2  body surface area of the subject, optionally at or about 300 mg/m 2 , daily, for 2-4 days. 
     
     
         81 . The method of any of  claims 1 - 80 , wherein the subject has received a lymphodepleting therapy comprising the administration of fludarabine at or about 30 mg/m 2  body surface area of the subject, daily, and cyclophosphamide at or about 300 mg/m 2  body surface area of the subject, daily, for 3 days. 
     
     
         82 . The method of any of  claims 1 - 81 , wherein the CAR comprises an antigen binding domain that binds to BCMA, a transmembrane domain, and an intracellular signaling region comprising a CD3-zeta (CD3ζ) chain. 
     
     
         83 . The method of  claim 82 , wherein the antigen binding domain is a single chain variable fragment (scFv). 
     
     
         84 . The method of  claim 82  or  claim 83 , wherein the antigen binding domain comprises a V H  and a V L  region, wherein the V H  region comprises a CDR-H1 set forth in SEQ ID NO: 56, a CDR-H2 set forth in SEQ ID NO:57 and a CDR-H3 set forth in SEQ ID NO:58, and the V L  region comprises a CDR-L1 set forth in SEQ ID NO: 59, a CDR-L2 set forth in SEQ ID NO:60 and a CDR-H3 set forth in SEQ ID NO:61. 
     
     
         85 . The method of any of  claims 82 - 84 , wherein the antigen binding domain comprises a V H  region that has the sequence of amino acids set forth in SEQ ID NO:36 or a sequence of amino acids that exhibits at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% to SEQ ID NO:36, and a V L  region has the sequence of amino acids set forth in SEQ ID NO:37 or a sequence of amino acids that exhibits at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% to SEQ ID NO:37. 
     
     
         86 . The method of any of  claims 82 - 84 , wherein the antigen binding domain comprises the V H  region sequence of amino acids set forth in SEQ ID NO:36 and the V L  region sequence of amino acids set forth in SEQ ID NO:37. 
     
     
         87 . The method of any of  claims 82 - 86 , wherein the antigen-binding domain is an scFv that has the sequence of amino acids set forth in SEQ ID NO:180 or a sequence of amino acids exhibits at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% to SEQ ID NO:180. 
     
     
         88 . The method of any of  claims 82 - 87 , wherein the antigen-binding domain is an scFv that has the sequence of amino acids set forth in SEQ ID NO:180. 
     
     
         89 . The method of  claim 82  or  claim 83 , wherein the anti-BCMA CAR comprises a V H  and a V L  region, wherein the V H  region comprises a CDR-H1 set forth in SEQ ID NO: 62, a CDR-H2 set forth in SEQ ID NO:63 and a CDR-H3 set forth in SEQ ID NO:64, and the V L  region comprises a CDR-L1 set forth in SEQ ID NO: 65, a CDR-L2 set forth in SEQ ID NO:66 and a CDR-H3 set forth in SEQ ID NO:67. 
     
     
         90 . The method of any of  claims 82 ,  83 , and  89 , wherein the antigen binding domain comprises a V H  region that has the sequence of amino acids set forth in SEQ ID NO:30 or a sequence of amino acids that exhibits at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% to SEQ ID NO:30, and the V L  region has the sequence of amino acids set forth in SEQ ID NO:31 or a sequence of amino acids that exhibits at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% to SEQ ID NO:31. 
     
     
         91 . The method of any of  claims 82 ,  83 ,  89 , and  90 , wherein the antigen binding domain comprises the V H  region that has the sequence of amino acids set forth in SEQ ID NO:30 and the V L  region has the sequence of amino acids set forth in SEQ ID NO:31. 
     
     
         92 . The method of any of  claims 82 ,  83 , and  89 - 91 , wherein the antigen binding domain is an scFv that has the sequence of amino acids set forth in SEQ ID NO:68 or a sequence of amino acids exhibits at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% to SEQ ID NO:68. 
     
     
         93 . The method of any of  claims 82 ,  83 , and  89 - 91 , wherein the antigen binding domain is an scFv set forth in SEQ ID NO:68. 
     
     
         94 . The method of any of  claims 82 - 93 , wherein the intracellular signaling region further comprises a costimulatory signaling domain. 
     
     
         95 . The method of  claim 94 , wherein the costimulatory signaling region comprises an intracellular signaling domain of CD28, 4-1BB, or ICOS, or a signaling portion thereof. 
     
     
         96 . The method of  claim 94  or  claim 95 , wherein the costimulatory signaling region comprises an intracellular signaling domain of 4-1BB, optionally human 4-1BB. 
     
     
         97 . The method of any of  claims 94 - 96 , wherein the costimulatory signaling region is between the transmembrane domain and the cytoplasmic signaling domain of a CD3-zeta (CD3ζ) chain. 
     
     
         98 . The method of any of  claims 82 - 97 , wherein the transmembrane domain is or comprises a transmembrane domain from human CD28. 
     
     
         99 . The method of any of  claims 82 - 97 , wherein the transmembrane domain is or comprises a transmembrane domain from human CD8. 
     
     
         100 . The method of any of  claims 82 - 99 , wherein the CAR further comprises an extracellular spacer between the antigen binding domain and the transmembrane domain. 
     
     
         101 . The method of any of  claim 100 , wherein the spacer is between at or about 50 amino acids and at or about 250 amino acids. 
     
     
         102 . The method of  claim 100  or  claim 101 , wherein the spacer is between at or about 125 amino acids and at or about 250 amino acids, optionally wherein the spacer is at or about 228 amino acids. 
     
     
         103 . The method of any of  claims 100 - 102 , wherein the spacer is an immunoglobulin spacer comprising all or a portion of an immunoglobulin constant domain or a modified form thereof. 
     
     
         104 . The method of any of  claims 100 - 103 , wherein the spacer comprises an IgG4/2 chimeric hinge or a modified IgG4 hinge; an IgG2/4 chimeric C H 2 region; and an IgG4 C H 3 region. 
     
     
         105 . The method of any of  claims 100 - 104 , wherein the spacer is set forth in SEQ ID NO: 29 or is encoded by a sequence of nucleotides set forth in SEQ ID NO:179. 
     
     
         106 . The method of  claim 100  or  claim 101 , wherein the spacer is a CD8 hinge. 
     
     
         107 . The method of any of  claims 1 - 106 , wherein the anti-BCMA CAR has a sequence set forth in any one of SEQ ID NOS: 126-177 or a sequence of amino acids that exhibits at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to any one of SEQ ID NOS: 126-177. 
     
     
         108 . The method of any of  claims 1 - 107 , wherein the anti-BCMA CAR has the sequence of amino acids set forth in SEQ ID NO:160 or a sequence of amino acids that exhibits at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to SEQ ID NO:160. 
     
     
         109 . The method of any of  claims 1 - 108 , wherein the CAR is encoded by the sequence of nucleotides set forth in SEQ ID NO:69. 
     
     
         110 . The method of any of  claims 1 - 107 , wherein the anti-BCMA CAR has the sequence of amino acids set forth in SEQ ID NO:161 or a sequence of amino acids that exhibits at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to SEQ ID NO:161. 
     
     
         111 . The method of any of  claims 1 - 107 , wherein the anti-BCMA CAR has the sequence of amino acids set forth in SEQ ID NO:152 or a sequence of amino acids that exhibits at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to SEQ ID NO:152. 
     
     
         112 . The method of any of  claims 1 - 107 , wherein the anti-BCMA CAR has the sequence of amino acids set forth in SEQ ID NO:168 or a sequence of amino acids that exhibits at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to SEQ ID NO:168. 
     
     
         113 . The method of any of  claims 1 - 107 , wherein the anti-BCMA CAR has the sequence of amino acids set forth in SEQ ID NO:171 or a sequence of amino acids that exhibits at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to SEQ ID NO:171.as 
     
     
         114 . The method of any of  claims 1 - 113 , wherein the anti-BCMA CAR binds BCMA, optionally wherein the BCMA is human BCMA. 
     
     
         115 . The method of  claim 114 , wherein the BCMA is membrane-bound BCMA expressed on the surface of a cell. 
     
     
         116 . The method of  claim 114  or  claim 115 , wherein the anti-BCMA CAR has a greater binding affinity for membrane-bound BCMA than soluble BCMA, optionally wherein the ratio of dissociation constant (K D ) for soluble BCMA and the K D  for membrane-bound BCMA is more than 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 200, 500, 1000, 2000 or more.